Abstract: Delirium is prevalent in geriatric surgical patients and is associated with significant morbidity, mortality, and cost. Many older surgical patients suffer from delirium postoperatively and, although numerous factors are likely involved, sedatives, general anesthetics, and depth of anesthesia have been strongly implicated. Nonetheless, the molecular mechanisms underlying the etiology of postoperative delirium remain unclear. A common feature of sedation and general anesthesia is that both decrease neural activity, the latter profoundly enough to induce coma and near-electrical silence on EEG, especially in the older patient. In preclinical models, blockade of neural activity stimulates a homeostatic response in neurons such that in less than an hour additional AMPA-type neurotransmitter receptors are inserted into the postsynaptic membrane of affected synapses?a phenomenon termed synaptic scaling. This scaling is a mechanism by which neurons increase the strength of their synaptic inputs in response to a decrease in global activity level, such that the increased strength of synaptic contacts restores neural circuit activity toward normal. Synaptic scaling requires TNF?, a cytokine best known as a mediator of inflammation, but one that is also a powerful direct neuromodulator. We have found that general anesthesia exposure causes transient TNF? induction in the young brain, and that this induction is impaired in the brains of old mice. We hypothesize that impaired induction of TNF? in old brain leads to impaired synaptic scaling and reduced neural activity upon emergence from anesthesia, ultimately leading to the clinical signs of delirium. To test this hypothesis, we will measure synaptic scaling and neural activity in the brains of young and old mice following general anesthesia. We will then use CX717, an ampakine that potentiates AMPA receptor activity, to artificially increase neural activity in aged mice during anesthesia, and then determine if increasing neural activity level in aged mice during anesthesia improves attention in an animal model for delirium. This research is clinically significant because it examines age- dependent changes in a fundamental property of neural homeostasis, investigates disrupted neural circuitry as a potential mechanism for postanesthetic delirium in seniors, and suggests ways to mitigate this morbidity in geriatric surgical patients.